The cause and development of chronic fatigue syndrome (CFS) are unknown, but may involve multiple organ and body systems, including neurological factors, psychological and psychosocial factors or influences, infections, immunological factors, endocrinal factors, genetic factors as well as several other less-common theories. No clinically-meaningful risk factor has been identified.[1]
Neurological abnormalities
CFS may involve neurological abnormalities, revealed by MRI and SPECT scans,[2] blood flow measurements,[3] studies of the serotonin signaling pathways,[4][5] and gene expression.[6] Levels of beta-endorphin, a natural pain killer, are low in some CFS patients.[7] Some of these findings resemble viral infection[8] and clinical depression, while others do not.[9]
Nervous system factors
Dysautonomia is the disruption of the function of the autonomic nervous system (ANS) which controls many aspects of homeostasis. In CFS this is mostly orthostatic intolerance - the inability to stand up without feeling dizzy, faint, or nauseated.[10] Research on CFS orthostatic intolerance shows associations with neurally mediated hypotension and postural orthostatic tachycardia syndrome,[11][12][13] as well as hypocapnia.[14] These conditions may cause blood to pool in the lower body when a person stands, reducing blood flow to the heart and brain. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.[15][16]
Psychoneuroimmunological interactions
The brain and immune system influence each other, especially in the HPA axis and sympathetic nervous system. Mental stress causes suppression of the immune system by hormones such as cortisol and epinepherine. Release of stress hormones, caused by diseases outside the brain, can result in neurological symptoms due to the influence of stress hormones on neurotransmitters. Neuropsychiatric disorders present in CFS may be related to auto antibodies to neuronal or endothelial (interior surface of blood vessels) targets,[17][18] or disordered cytokine production by glial cells within the central nervous system.[19]
Psychological and psychosocial
The possible involvement of psychological factors within CFS is both unclear and contentious,[20][21] with several psychological and psychosocial factors having been theorized. Some individuals with CFS firmly reject any psychological involvement and believe strongly that their condition has a physical cause.[22]
Behavioral
In one study, CFS patients were found to have consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints, supporting a hypothesis that behavioral factors might have a role in the etiology of CFS.[23]
High levels of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS.[24][25] It has been hypothesized that in CFS the health threat is no longer the illness, but rather anything that threatens to disrupt a precarious accommodation to it. Due to established vicious circles, attempts at threat regulation may become inadvertently self-defeating, promoting the threats they attempt to diminish.[26]
Neuroticism and introversion have previously been reported as risk factors for developing CFS.[27] A recent systematic review of personality and CFS found an association with neuroticism, but stated that it was often accounted for by co-morbid depression and levels were similar to those in patients with other chronic diseases, and found no firm evidence for introversion.[28]
Cognitive behavioral model
According to the cognitive-behavioral model of illness, the patient's interpretation of symptoms plays an important role in perpetuating the illness. Catastrophic interpretations of symptoms, the belief that symptoms are beyond the patient's control and excessive emotional reactions may accentuate the physiological changes giving rise to symptoms. The cognitive-behavioral model differs from the extreme psychological model which proposes that illness symptoms are exclusively mental.[29] In response to a version of the cognitive behavioral model described in the book "Chronic Fatigue and Its Syndromes", the authors of a status report on CFS state, "Although this model may explain continued illness in some CFS patients, it certainly does not pertain to all CFS patients and is thus not too satisfactory."[30]
Fixation
Some research suggests that CFS may be perpetuated when patients fixate on a physical cause for their symptoms or when exercise is avoided.[27][31]
Illness behavior
A lack of support, or the reinforcement of illness behavior by social networks, may be associated with delayed recovery for some patients.[27]
Mood disorders
There are clinical overlaps and differences between CFS and clinical depression. Current mood disorders occur in 18.9% of CFS patients compared to 3.9% of the general population.[32] Previous psychiatric disorders or shared risk factors for psychiatric disorders may have an etiological role in some cases of CFS.[33] The presence of multiple comorbid disorders could be a marker for psychological influences on etiology.[34] Neuropsychological impairments could be involved in CFS,[35] and neuroendocrine studies and brain imaging have confirmed the occurrence of neurobiological abnormalities in most patients with CFS.[36] Findings of increased autoimmune antibodies against phospholipids (phosphatidyl inositol) in CFS and depression may underpin the similarities and comorbity between the two disorders.[37]
Sensitization
Central sensitization could be responsible for the sustaining pain complaints in CFS. Elevated concentrations of nitric oxide are present in the blood of CFS patients, and brain imaging shows brain abnormalities. Catastrophizing, avoidance behavior, and somatization may result in, or are initiated by, sensitization of the central nervous system.[38]
Stress and trauma
The majority of people who experience stress or trauma do not develop CFS, but these factors may increase the likelihood of acquiring CFS.[39][40][41] A study of twins found both stress and genetics could contribute to CFS,[42] and anxiety disorders have been associated with CFS in 5-15 year olds.[43] CDC studies found gene mutation and abnormal gene activity levels in CFS patients that may relate to the function of the hypothalamus-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response.[44]
Childhood abuse, stress, or trauma may be predisposing factors to CFS.[1][45] Another study supports the association with childhood abuse for idiopathic chronic fatigue or chronic fatigue explained by a psychiatric diagnosis or medical condition, but not with CFS.[46]
Infections
Viral and bacterial infections have been associated with CFS but their influence on etiology and pathophysiology is controversial. The more conservative conclusions have been that these are not directly responsible for causing CFS but are co-infecting pathogens. Some researchers say there is a higher winter onset of CFS, and their hypothesis is that symptom onset is precipitated by a viral infection in some people.[47][48] Other experts say that while symptoms of CFS can occur after severe infection, strong data does not yet exist to support an infectious process in disease maintenance.[30]
Several bacteria have been associated with CFS. Q Fever, caused by Coxiella burnetii, can cause a post infectious fatigue syndrome resembling CFS.[49][50][51] CFS patients reportedly have higher rates of Chlamydia pneumoniae infection than controls.[49][52] The possible influence of mycoplasma is disputed, with reports for[53][54][55][56] and against.[57] A review concludes the role of mycoplasma as causal agents, cofactors, or opportunistic infections is not clear.[58] Gram-negative enterobacteria and increased intestinal permeability may be associated with severity of CFS symptoms.[59] Multiple bacterial and/or viral co-infections (mycoplasma, Chlamydia, HHV-6) have been associated with increased severity of signs and symptoms.[52]
Enteroviruses like the Coxsackie virus[60] and Polio virus have been associated with symptoms resembling CFS. A number of studies have investigated enterovirus infections in CFS patients, but the results are contradictory and no causal relationship has been demonstrated.[61] Epstein-Barr virus (EBV) is present in 90% of the general population and sometimes causes infectious mononucleosis (glandular fever). EBV was once the principal suspect in chronic fatigue illnesses,[62][63] but mixed study results[64][65][66] have led to the current view of EBV in some patients as either a post infectious causal factor[49][67] or a factor in reactivation.[68] Other viruses implicated by some researchers include Ross river virus;[69] Borna disease;[70] Parvovirus B19;[49] and herpes viruses Cytomegalovirus (HHV-5),[71] Human Herpesvirus Six (HHV-6), and HHV-7.[72][73] A role for herpes viruses in CFS is controversial.[74][75]
Retroviruses
Evidence that retroviruses were associated with CFS was described in 1991 when retrovirus sequences similar to human T-lymphotropic virus (HTLV) type II was reported in the blood of a subset of CFS patients and not in healthy controls.[76] However, many other CFS studies did not replicate these findings or find evidence of infection with human retroviruses.[76]
More recently, differing results on the association of gammaretroviruses and CFS have been published. The newly discovered xenotropic murine leukemia virus-related virus (XMRV) was detected in the blood of 67% of CFS patients but in only 3.7% of healthy controls, and the study published in Science in 2009. The authors also reported cell culture experiments showing XMRV derived from patients was infectious, and hypothesized that XMRV might be a causal factor in CFS or simply be a passenger co-infection.[77] Four follow-up studies - two from the UK, one from the USA and one from the Netherlands - detected no XMRV in CFS patients. The researchers from the first concluded, "we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K."[78][79][80][81]
In August 2010 a study in PNAS reported that researchers from the FDA/NIH found MLV-like virus gag gene sequences in 87% of patients and 7% controls. Although the study did not find XMRV itself, the authors conclude that their findings "clearly support" a role for MLV-like viruses in chronic fatigue syndrome and point out that none of the followup studies to date have attempted to replicate all of the original study's multiple methods used to detect XMRV.[82]
Immunological dysfunction
Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,[83] but they may not represent the entire picture[84] and some CFS experts doubt they are responsible.[30]
Autoimmune disorders[85][86] and allergies or food intolerance[87] have been reported in CFS sufferers. Gene expression changes have been reported in the white blood cells of CFS patients. This is consistent with the theory of immune system activation [88] and abnormal types of antiviral protein RNase L and are postulated to affect sleep-wake cycles and exercise capacity.[89] High levels of Th2-type cytokines and the cells that make them are also found in CFS.[83][90][91][92] The resulting increased antibody production may explain some immune dysfunctions in CFS. A reduction in the opposite Th1 response has also been reported[93][94][95] with implications for altered Th1/Th2 balance. Therapeutic alterations of cytokine expression patterns are being investigated.[90][96]
In contrast, immunodeficiency disorders characterized by abnormal T-cell subset ratios, levels of immunoglobulins, and hypoallergic responses on the French Multitest have been reported in CFS.[90] Patients with lower natural killer cell activity report less vigor, more daytime dysfunction and more cognitive impairment.[97] There is also evidence that people with CFS have improper gene expression including both over-expression and under-expression of genes involved in the immune system (see the "gene expression" section below).
Altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and neurological symptoms found in CFS.[98] The monocyte/macrophage which crosses the blood brain barrier is an essential candidate cell in the study of psychoneuroimmunology.[99]
Endocrine system
A 2006 update in the journal Current Opinion in Psychiatry stated, "Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered."[100] Alterations in serotonin signaling can lead to physiologic and behavioral changes. Polymorphisms in genes related to serotonin pathways may indicate genetic predisposition in the pathophysiology of CFS.[101] Some researchers think cold therapy can increase serotonin levels to treat CFS.[102]
Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders. The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythm and modulated by factors such as stress, digestion or illness. It is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body. Other changes seen in CFS include low cortisol,[103] enhanced sensitivity of the HPA axis to negative feedback,[104][105] and possibly an altered diurnal cortisol rhythm.[106] These results may not apply in all CFS,[107][108] and the HPA axis abnormalities could be cause or a result. Some researchers say they are a likely factor in symptom propagation in CFS.[109]
Gene expression and polymorphisms
CFS-related abnormalities in gene expression have been studied.[44][110] Changes in genes involved in transport (both vesicle-mediated and protein transport),[111] metabolism,[112] immune regulation, neuronal function, mitochondrial function, apoptosis and other processes have been reported.[113][114][115] The CDC has said these changes could be involved in CFS.[44] Some of the symptoms of gene expression differences may be treatable with existing drugs.[116] Some researchers think gene expression studies could make possible better categorization of CFS[117][118] and even help with differential diagnosis.[119]
A 2007 review stated that certain genetic polymorphisms might be regarded as predisposing factors.[120] Studies have shown genetic differences in genes of CFS patients and healthy controls in the central nervous,[101][121] endocrine,[122][123][124] immune [125][126] and cardiovascular systems.[127]
Exercise findings
In a large national birth cohort study, the risk of developing CFS as an adult was inversely correlated with childhood exercise, but no association was found for other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.[141] However, a similar study found that an increased level of exercise in childhood and early-adulthood is a risk factor.[142]
Abnormal lactic acid responses to exercise in some CFS patients[143][144][145] have been suggested to be a factor in CFS because it is commonly believed to be responsible for muscle fatigue.[146] However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.[147]
Oxidative stress
Oxidative stress, an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage is consistent with CFS symptoms, especially relating to fatigue, pain and exercise intolerance.[128] Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance, reflected in abnormal heart rate variability.[129]
NO/ONOO– cycle disease
It has been tentatively suggested that defects in the nitric oxide (NO) and peroxynitrite (ONOO–) cycle may lead to chronic fatigue.[130]
Metabolic disorders
Metabolic disorders and mitochondrial disorders can cause symptoms that resemble CFS.[131] Mitochondrial disturbances have been discovered in patients diagnosed with post-viral fatigue syndrome.[132] Folate deficiency may also mimic CFS symptoms.[133][134]
Essential fatty acid deficiencies
Essential fatty acid levels: Several studies published between 1990 and 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with post-viral fatigue syndrome or CDC-defined CFS.[135][136][137][138] One study conducted in 1999 on Oxford-criteria-defined CFS patients (Warren et al.) found no significant differences in fatty acid levels between treatment and placebo groups.[139] A review of CFS treatments compared two studies of essential fatty acids, concluding that there is insufficient evidence to recommend it as a treatment for CFS.[140]